Calcioum and Phosphate Homeostasis/Vitamin D Flashcards
Where is the body’s calcium stored?
- The vast majority (99%) of the body’s calcium is stored as hydroxyapatite crystals in the endoskeleton, thereby playing a crucial structural role.
- The remaining 1% of the body’s calcium serves other important functions.
What does calcium do?
- Calcium is essential for many fundamental processes including fertilization, vision, muscle contraction, nerve conduction, blood clotting, exocytosis, cell division, activity of enzymes, and intracellular signaling.
- The concentration of calcium (as well as phosphate) in the cellular and extracellular fluids must be maintained within a relatively narrow range (total Ca: 8.5-10.5 mg/dL; P: 3.0-4.5 mg/dL).
The complex system of controls for calcium and phosphate homeostasis involve […], […] and […].
The complex system of controls for calcium and phosphate homeostasis involve parathyroid hormone (PTH), calcitonin (CT) and vitamin D (active form = 1,25-dihydroxyvitamin D3).
•and estrogen!
PTH and Calcium Homeostasis
- The acute modulation of calcium is mediated by PTH.
- A low plasma concentration of calcium stimulates the release of PTH by the parathyroid glands.
- PTH, in turn, causes the resorption of calcium from the pool in bone while also enhancing the reabsorption of calcium in the kidney.
- PTH produces an indirect effect on intestinal calcium absorption by increasing the conversion of vitamin D to its active form in the kidney
Vitamin D and Calcium Homeostasis
- Long-term (chronic) adjustments in plasma calcium are accomplished by altering the absorption of dietary calcium, thus preventing a significant drain on the skeletal mineral.
- Vitamin D regulates intestinal calcium absorption by stimulating calcium uptake as well as by promoting renal reabsorption.
Estrogen (and Testosterone) in Calcium Homeostasis
•The role of estrogen (and testosterone) in this scenario is the prevention of bone resorption.
Phosphate Homeostasis
- In terms of phosphate homeostasis, vitamin D promotes intestinal absorption and renal reabsorption.
- By its concomitant effects on calcium and phosphate, vitamin D maintains the Ca•PO4 matrix, thereby favoring bone mineralization.
- The lack of vitamin D leads to bone loss – rickets in children and osteomalacia in adults.
- With the primary signal for the release of PTH being a low concentration of calcium, the marked mobilization of phosphate during resorption of bone, together with the increased intestinal absorption of phosphate due to vitamin D, could potentially lead to hyperphosphatemia.
- To offset this problem, PTH prevents hyperphosphatemia by diminishing phosphate renal reabsorption in the proximal tubule.
- Consequently when plasma PTH is elevated, phosphaturia can be observed.








PTH Biosynthesis and Secretion
•PTH is initially biosynthesized as prepro-PTH. The biosynthetic and secretion pathway for PTH, in the chief cells of the parathyroid gland, resembles that of prepro-insulin translation and sequential cleavages to insulin. Processing leads to storage in granules that ultimately fuse with the cell membrane to release their contents. Unlike insulin, but like glucagon, PTH has a single polypeptide chain.

The biosynthesis and secretion of PTH is regulated by […].
- The biosynthesis and secretion of PTH is regulated by plasma calcium.
- The calcium sensor is a Gq protein-coupled receptor that acts to “trap” serum calcium.
- Like all G-protein coupled receptors, the CaR has 7-transmembrane helices.
- Activated Gq, stimulates phospholipase C that cleaves phosphatidylinositol in the inner leaflet of the plasma membrane to promote the formation of the second messenger, inositol trisphosphate (IP3), as well as diacylglycerol (DAG).
- IP3 promotes release of calcium from intracellular stores in the endoplasmic reticulum and, together with the likely influx of extracellular calcium, inhibits secretion of PTH.
- This elevated intracellular calcium in some way blocks fusion with the plasma membrane of the PTH-containing storage granules.
- Additionally, elevated 1,25(OH)2D3 inhibits transcription of the PTH gene to decrease production of PTH.
-Since 1,25(OH)2D3 raises plasma calcium, its inhibitory effect on PTH prevents hypercalcemia.
•When the plasma concentration of calcium is low, this inhibitory mechanism is inactive.
Biochemical Action of PTH in the Kidney
- PTH in the circulation binds to its receptor on cells in the target tissues (i.e., bone, kidney). The activated PTH receptor complexes with Gs protein and therefore is coupled to activation of adenylyl cyclase to increase cAMP.
- Because the kidney is a primary site of PTH action, PTH infusion sharply increases urinary excretion of cAMP in humans.
- This rise in cAMP precedes a marked augmentation of urinary phosphate that results from PTH inhibiting renal phosphate reabsorption.
- In the renal proximal tubule, phosphate is reabsorbed on a sodium-phosphate cotransporter that is driven by the sodium gradient.
- PTH reduces phosphate reabsorption by decreasing the number of transporters in the membrane.
Biochemical Action of PTH - Bone
- PTH in the circulation binds to its receptor on cells in the target tissues (i.e., bone, kidney).
- The activated PTH receptor complexes with Gs protein and therefore is coupled to activation of adenylyl cyclase to increase cAMP.
- In bone, PTH acts via cAMP in osteoblastic cells.
- The osteoblasts, in response to PTH, increase resorptive (paracrine) factors like IL-6 that acutely stimulate osteoclastic resorption of bone mineral.
- PTH also induces, on the surface of osteoblasts, the expression of RANKL [receptor activator of NF-kB ligand]/ODF [osteoclast differentiating factor], which causes a net enhancement in the number of osteoclasts.
- The ligand binds to a receptor located on the surface of monocytic osteoclast progenitor cells (MOPs). RANKL/ODF, in combination with M-CSF (macrophage colony stimulating factor) that binds to the c-Fms receptor, causes the precursor cells to differentiate and fuse to form multinucleate osteoclasts.
- This effect increases the capacity for bone resorption.

Calcitonin
- Calcitonin reverses the action of PTH on bone resorption to cause a fall in blood calcium.
- CT secretion by the C-cells of the thyroid is enhanced by high calcium in the blood.
- CT is physiologically important postprandially, where it prevents hypercalcemia by shutting down calcium mobilization from bone.
- In addition, CT serves as an important counter-regulatory hormone to PTH to prevent hypercalcemia and kidney calcification.
- CT is also found in the brain and spinal fluid where it may function as a neuromodulator. Intraventricular injection of CT inhibits feeding behavior in animals. CT could be a “calcium satiety hormone” analogous to the general satiety role proposed for CCK in brain. Consistent with this notion is the fact that the CT structure reveals a C-terminal amidation that is a signature for neuromodulator peptides; its N-terminal, intrachain disulfide is also characteristic of such molecules. This provides another example of a possible link between the endocrine function and behavioral response/CNS activity of peptide neuromodulators.
CT Secretion
- CT is secreted by the thyroid C-cells under conditions of hypercalcemia.
- The thyroid C-cells contain a calcium sensor (receptor, CaR) that is identical to that in the parathyroid chief cells. In this instance sensing of calcium increases secretion of CT.
- When serum calcium is low, CT secretion is shut off.
Biochemical Action of CT - Bone
- In bone, CT operates via receptors that are coupled to adenylyl cyclase through Gs and thereby raises the cAMP concentration.
- Although the receptors are distinct, and each is specific for its respective PTH or CT ligand, how can CT act on bone to lower calcium resorption by opposing PTH when both function via Gs to raise cAMP?
-The two opposing hormones can act via the same signal transduction pathway in the same tissue by affecting different cell types.
- CT raises cAMP in bone resorbing osteoclasts to directly inhibit their activity, while PTH increases cAMP in osteoblasts to cause them to secrete paracrine resorptive factors that in turn activate osteoclasts.
- Thus CT blocks PTH action distally at the osteoclast.

CT Gene
- The CT gene also generates another neuropeptide, calcitonin gene related peptide (CGRP).
- CGRP is a neuromodulator and is the most potent and persistent vasodilator known.
- Either CGRP or CT can arise from the CT gene by alternative splicing of mRNAs.
- In thyroid “C” cells, the primary transcript is processed and spliced to yield an mRNA that is translated into prepro-calcitonin, while in certain neurons in the brain and spinal cord, the transcript is processed differently to exclude the CT coding exon and substitute the CGRP coding exon – with the result being prepro-CGRP.
Vitamin D
•Though Vitamin D is considered a fat-soluble vitamin along with A, E and K, this classification is somewhat tenuous because, with adequate sunlight exposure, humans do not require a daily dietary supply. In this way Vitamin D is obtained as an “exo-prohormone” when UV light photolyzes 7-dehydrocholesterol in the epidermis (non-enzymatic) to vitamin D3.
Dietary Vitamin D
- In individuals who have insufficient exposure to UV light including use of high SPF sunblockers, dietary sources of Vitamin D are critical to avoid deficiency.
- Vitamin D is found in fortified food products, oily fish [e.g., salmon], and eggs [though a minor source].
- Infant formulas must also contain sufficient vitamin D. In the US, milk fortified with vitamin D2 (ergocalciferol, a plant steroid) or vitamin D3 (cholecalciferol) is the principal source of dietary vitamin D.
- In other parts of the world, cereals and bread products may be fortified.
- Fat-soluble vitamins, such as vitamin D, are incorporated into micelles, absorbed by intestinal enterocytes and packaged into chylomicrons.
- The chylomicron remnant travels to the liver where it delivers the fat-soluble vitamins along with cholesterol.
- A variety of malabsorption disorders can impair uptake of digested materials and lead to a nutritional deficiency of vitamin D as well as other fat-soluble vitamins.

Processing of Vitamin D to its Active Form
- Vitamin D itself does not act upon intestine, kidney and bone, but must first be bioactivated via a two-step metabolism in liver and kidney.
- The kidney activation of vitamin D is the key reaction.
- Initial modification occurs in the liver, where vitamin D3 is hydroxylated to the intermediate form, 25(OH)D3.
- This intermediate is then converted, by a kidney mitochondrial P450 1-hydroxylase enzyme (1-OHase) into one, 25(OH)2D3, the most potent form of vitamin D.
- When blood calcium and/or phosphate are elevated and the kidney 1-OHase is feedback repressed, the 25(OH)D3 intermediate is converted instead to the inactive metabolite 24, 25(OH)2D3.
- Formation of 24,25(OH)2D3 occurs in the kidney in a reaction catalyzed by 24- hydroxylase.

Physiological Regulation of Vitamin D Production
- low dietary calcium?
- low dietary phosphate?
- active growth in children?
- pregnancy/lactation?
- Increased circulating 1,25(OH)2D3 raises calcium (and phosphate) to meet augmented needs of the minerals for the fetus in pregnancy, in milk for lactation, or to compensate for a relative dietary lack of the mineral.
- Estrogen inhibits bone resorption and directs 1,25(OH)2D3 action more to the gut, where calcium and phosphate are acquired from the diet.
- Physiologically, feedback loops of increased calcium (or phosphate) shut down production of 1,25(OH)2D3 or the hormone can limit its own biosynthesis at the parathyroids (decreased PTH gene transcription) or the kidney.
- When calcium (or phosphate) are high so that 1,25(OH)2D3 is elevated, 25(OH)D3 is metabolized to the inactive 24,25(OH)2D3 form

Functions of Vitamin D
- Vitamin D, in addition to stimulating intestinal calcium absorption, renal calcium conservation and bone calcium resorption (hypercalcemic actions), stimulates intestinal absorption of phosphate and renal reabsorption of phosphate (hyperphosphatemic actions).
- In this way, vitamin D prevents rickets in children by raising the ion product Ca•PO4 in blood.
- Improving the Ca•PO4 matrix elicits proper bone mineral deposition through hydroxyapatite crystallization on the type I collagen organic matrix.
- When stressed by weight bearing, rachitic bones bend, but do not fracture in the traditional sense. Instead they incur numerous radiographically detectable lesions called pseudofractures.
